Process for producing chroman compounds



Patented June 10, 1947,

UNITED STATES PATENT OFFICE PROCESS FOR PRODUCING CHROMAN COMPOUNDS Y Lee Irvin Smith apolls, Minm, verslty of Minn assign esota, corporation of Minnesota No Drawing. Application July SerialNo. a claims, (01. 260-333) of the latter, that new which are useful as antioxidants, biological control factors,

method of manufacture therefor.

Thus when compounds of type are reacted with hydroqumone compounds such s hydroquinone derivatives or substituted the invention to provide such amethod of manufacture. The-hydroquireferred to herein may also be methods for producing the prod cts of thi invention. Y

the conjugated diene chloride, zinc chloride, mercuric chloride, phosand Herbert E. Ungnade, Minneors to Regents of the Uni Minneapolis, Minn., a

, '2 It is to be understood, of course that some conditions of are those inherent and products here- Other and further objects and implied by the processes inafter described and claimed.

According ent invention formicacid, or acetic acid: acid chlorides, or

anhydrides such as acetyl chloride or acetic an hydride; a substituted organic acid such ashaloreaction mixture is permitted to cool. a

The mechanism of the, reaction between the hydroquinone monomethylether and the dimethyl butadiene and the structure of the resultant 2-2-3 trimethyl 6 methoxy chroman are to be as follows:

product believed cmo cn= The crude reaction product, which is a viscid brown mass, is then dissolved'in ethyl ether and the ether solution washed with Claisens alkali I CH: CH3

(potassium hydroxide, methanol and water) and then with water. The ether layer which separates is then dried over calcium chloride and the ether. is then distilled off! The residue which remains is a crude dark colored liquid, The crude liquid is then distilled in a high vacuum and yields a water white liquid product having a boiling point of 50-55 C. at l 10 mm. mercury pressure.

Example II A mixture of 8.2 grams dimethyl butadiene and 12.4 grams hydroquinone monomethylether are dissolved in 10 grams glacial acetic acid. The mixture is saturated with dry hydrogen-chloride at C. and then allowed to react by standing in the cold for 18 hours.

The mechanism of this reaction and the structure of the resultant product are believed to be the same as that set forth in Example I. The reaction which is finished by warming in a steam bath, yields a dark oily substance. A solution of 40% KOH is then added While simultaneously cooling. The mixture is then washed with water, separated by the use of ether and purified, as in Example I. The final product is a water white oil. This compound is likewise 2-2-3 trimethyl 6 methoxy chroman.

Example III A mixture of grams trimethylhydroquinone, 100 "cc. glacial acetic acid and 1 gram zinc chloride is heated to 100 C. under efficient reflux at atmospheric pressure, and while refluxing 10 grams of isoprene is added. The hot mixture is permitted to stand and is then reacted by further refluxing. One drop of concentrated HZSOA is then added and the refluxing continued for one hour.

The mechanism of the reaction between the trimethyl hydroquinone and isoprene and the structure of the resultant product 2-2-5-7-8 pentamethyl 6 hydroxychroman are believed to be as follows:

CH3 (3H3 on 0 on em -01: n. a on, 3 (311 om 110- o no H2O CH3 l CH3 1 CH:

The reaction mixture is then permitted to cool and is then poured into water. A solid which forms is filtered out and recrystallized from dilute ethyl'alcohol. The yield is about I grams of crystals having a melting point of 94-945 C.

Example IV (the diene corresponding to of chlorophyll) is substituted When phytadiene the alcohol, phytol,

for the dimethyl butadiene of Example I, a reaction similar to that therein set forth occurs.

Trimethylhydroquinone (0.5 g.) and phytadiene (2 g.) are dissolved in a mixture of formic acid (5 g.) and acetic acid was refluxed for six hours. The mixture should then be cooled, poured into water, extracted with ether and the ether solution washed with water until the washings are neutral. The ether layer should then be dried over sodium sulphate, filtered and the ether evaporated. The crude product (2 g.) is a dark, viscousoil, which is believed to be alpha tocopherol. The product boils at about 145 under 1x 10- mm.

Example V A mixture of 18 grams hydroquinone monomethylether and 11 grams of isoprene in 25 cc. of acetic acid was saturated with dry hydrogen chloride gas at 0 C. The mixture was permitted to stand in the cold (approximately 0 C.) for 12 hours and was then warmed on a steambath for 30 minutes, during which the temperature of the mixture gradually approached the temperature of the steam which was C. The mixture was then removed from the steambath and permitted to cool to room temperature, at which time an excess of 40% potassium hydroxide was added. The solution was then thoroughly extracted with ethyl ether which served to dissolve the resultant product, and the ether layer was then removed, washed with water, and dried over calcium chloride. The ether solution carrying the product of the reaction was then distilled on a steam-bath at approximately 32 C. and the residual oily product recovered. The resultant oil was fractionally distilled under 0.1 millimeter of mercury pressure and yielded two fractions, the first being recovered between the boiling points of 74 C. and 80 C. and the second fraction between C. and 107 C. The second fraction was apparentlyan intermediate l-(ohydroxy-m-methoxy phenyD-B methyl-3-chloro butane and was converted into the composition of the first fraction by cyclization with potassium acetate in methanol.

Example VI of 2.74 grams trimethylhydrograms pentadiene and 0.3 gram zinc chloride in 30 cc. glacial acetic acid was refluxed for one hour, one drop of concentrated sulphuric acid being added during refluxing. After refluxing the resultant mixture. was poured into cold water. Solid material separated out when the mixture was poured into water and filtering. The solid residue was several refrom the petroleum ether a relatively pure product having a melting-point of 113-114 C. was obtained. It is believed that the resultant product was 2 ethyl-5,7,8 trimethyl- 6-hydroxy chroman.

The diene constituents for the procedures herein described may be produced from the cor- A mixture quinone, 1.23

soluble crystallizations responding alcohol either as a preliminary reaction or in situ in the reaction medium wherein the hydroquinone compound is present. Where produced in situ the hydroquinone inthe alcohol ingredient, the diene intermediate, if produced, being transient. Some evidences indicate that with certain alcohols, at least, the reaction does not include the formation of a diene intermediate, and that the reactionis directly between the hydroquinone compound'ingredient and the alcohol ingredient. v I

The compounds which are adaptable for use in the present invention in the place of the dienes (2 g.) and the solution aforementioned are those link presenting double bond ages. Thus any alcohol, such as an allylic alcohol. or any compoundwhich will produce a diene constituent either directly by the useof acid catalysts and/or heat, or after rearrange, ment in the presence of acids and/or by heating. may be used in this synthesis. 'Thus :l'or the source of the diene constituent we may use an ene-ol, e. g. an aliphatic alcohol in which at least one double bond is present, such as primary allylic alcohols having the general structure where R. orR' are hydrogen atoms or alkyl radicals, or tertiary a'llylic alcohols having the general structure in which X may be either a a halogen. Or as the source or the diene constituent we may likewise use a dihydric alcohol or a halide such as the 1,2 diols or 1,2 dihalides having the general structure 1,3 dihalides having the gen- .X I 1"! where either X1 or X: or both may be a hy-- droxyl group or halogen.

When utilizing the dihaiide according to this procedure the selected diene yielding compound is substituted for the diene constituent and the reaction carried out as before in the presence of an acid dehydratingcatalyst or-by heating in the absence or a catalyst. When utilizing the diols it is preferred to diene constituent and utilize the thus prepared diene constituent with the hydroquinone compound in producing the new products of the present invention.

Example VII A mixture of 1 gram trimethylhydroquinone, 1 cc. allyl alcohol, 0.3 gram anhydrous zinc chloride and 5 cc. benzene was sealed in a Carius tube and heated at 200 C. for 3% hours. The resultant reaction mixture was shaken with petroleum ether and water, and the ether layer hydroxyl group or or the 1,3 ,diols or era] structure containing the reaction product, separated and allowed to stand for 24 hours. It was then filtered and evaporated to isolate the thick residual oil reaction product. The residual oil crystallized on cooling, and the crystalline residue was dissolved in ethyl ether and purified by steam distillation, the distillate yielding a crystalline solid having a melting pointof 124.5-125.5 C., the yield was about 200 mg. The product wasrecrystallized from petroleum ether and after thus purified had a melting point of l27-128 C. The

product is believed to be 2,4,6,7-tetramethy1 5- hydroxy coumaran.

E'azami le VIII A mixture or 1 gram trimethylhydroquinone, 1 cc. methylvinyLcarbinol, 0.3 gram zinc chloride and 5 cc. benzene was sealed in a Carius tube and heated to 200 C. 1on3 hours. The product prepare the conjugated present was dissolved out with petroleum ether and the solution was allowed to was then filtered and evaporated and the residue was crystallized i'rompetroleum ether and then from aqueous ethanol. The thus purified product melted at 119.5 to 120.5 C. and was believed to be 2,3,4.6,7- pentamethyl 5-hydroxy coumaran.

Example IX 2 grams of trimethylhydroquinone, 2 cc. ethylvinyl car-binol, 0.6 gram zinc chloride and 5 cc. benzene was sealed in a Carius tube. and heated to 150 C. for one hour and then to 200 C. for

a melting point of 88'-89 C. and is believed to be 2,4,6,'7-tetramethyl 3 ethyl-5 hydroxy coumaran. this procedure indicate that the mercury pressure. The fraction distilled oil between 110-115" C. is believed to be a; substituted hydroxy chroman.

Example XI v tillation in high vacuum.

The product produced in example is a pale yellow fairly viscous oil and whenbiologically assayed for its vitamin E activity was found .to be active in 3 mg. doses. That is to say, this examplewas fed in standardized conditioned female test rats, litters of live young were producedin 100% of all rats stand for 24 hours. It

accordance with the rotatory about the derivatives of fed, and the activity of the product was equal, weight for weight, to natural alpha tocopherol.

However, the product of the present example is not identical with natural alpha tocopherol since the former is the number two carbon atom, while the latter is same. The new product of this procedure may thus, with reason be known as racemic alpha tocopherol.

The non-identity is also evidenced by the fact that the allophanate derivatives of the product produced by this example and the allophanate natural alpha-tocopherol melt at 168-170" C. and 157-160" C. respectively, and the melting point of mixtures of allophanate derivatives is between these melting points.

In the present example the glacial acetic acid, a polar solvent, apparently acts not only as a solvent but also as a catalyst. Other examples of polar solvents suitable for use in the reactions of the present invention are formic acid, propionic acid and the like compounds.

Example XI I .lieved consisted primarily of diallylation product the following structure:

probably having In this and other examples of the present invention the benzene, a non-polar solvent, served the reacting ingredients. Other non-polar solvents suitable for use tion are toluene, xylene, decalin' and the like.

Example XIII which is described by Bell- 464, and otherwise known as tetrahydrofarnesol, having When nerolidol, stein, vol. 1, page the allylic isomer of the structure Example XIV The product produced in accordance with Example VIII was boiled with an excess of acetic anhydride and the acetate thus produced separacemic (not-rotatory) about i in this inven-' quinone compound ingredient may The ace- C. and is useful for many purposes, since the ester is not readily oxidized as is the parent substance of Example VIII.

Similar esters may be prepared from any of the products produced in accordance with the procedure herein set forth provided these products contain a free hydroxyl group. Thus the products produced in accordance with Examples VII and. XII hereof. and other examples may likewise be esterlfied. The propionate, butyrate, palmitate, stearate and the like esters may also he prepared from the products hereof and are particularly useful where stability is important.

In the procedures herein described the hydroif desired be a mono-ether such as the methyl, ethyl, propyl, allyl, cyclohexyl or the like or a mono-ester, such as an acetate, propionate, benzoate, allophanate, palmitate or the like, which ethers or esters have at least one position vacant ortho to a free hydroxy group of the hydroquinone nucleus. The ether or ester grouping remains throughout the reaction and, if desired, is cleaved from the resulting product by any of the well known methods. Thus the ester group may be cleaved by hydrolysis with alkali, for example, as described by Evans et al., Journal of Biological Chemistry, 113, 322 (1936), and the ether group may be cleaved by the use of a Grignard reagent, for example, as described in Chemical Abstracts, vol. 26, pages 5084-5, and vol. 2'1, pages 276-! and page 2944. It is to be understood of course, that for some uses, it is desirable to leave the ether or ester grouping in place, while for other uses it is desirably removed.

In each of the foregoing examples the hydroquinone compound used is either a substituted hydroquinone or a derivative of hydroquinone. Thus in Examples I and II the derivative, hydroquinone monomethylether, was used and in Examples III, IV and others of the examples the substituted compounds, trimethylhydroquinone or m-xylohydroquinone, were used. Accordingly where the term hydroquinone compound is used in the specification and claims, it is intended to mean alkyl substituted hydroquinones or the hydroquinone ethers and esters such as those herein enumerated.

Certain of the products containing a free hydroxyl group, and made according to the process of the present invention, are active antioxidants and may be used for the purposes for which antioxidants have heretofore been employed, and

being structurally identified with the tocopherols,

they are useful as such. The term tocopherols" refers to naturally occurring substances having biological (vitamin E) activity. The term was introduced into the literature in the Journal of Biological Chemistry, volume 113, page 321, 1936.

The present application is a. continuation in part of our application Ser. 211,077, filed May 31, 1938, Patent 2,249,054, issued July 15, 1941.

Many and various modifications will suggest themselves to those skilled in the art and it is intended that these may be used in modification of the procedures and products herein set forth without departing from the spirit of the invention described and claimed.

We claim:

1. A process for producing chroman compounds which comprises reacting a gamma-gamma-diaikyl-substituted allylic alcohol .having a double bond in the beta-gamma position to the hydroxyl which comprises class consisting of alkyl-substituted-para-di-hydroxy benzenes and their mono ethers and mono esters, said reaction being carried'out in the presence of a solvent and in the presence of an acidic catalyst.

3. A process for producing chroman compounds reacting a gamma-gamma dialkyl-substituted allylic alcohol having a double bond in the beta-gamma position to the hydroxyl group and a mono ester of an alkyl-substitutedpara-di-hydroxy benzene having one position vacant ortho to the free hydroxyl group, in the presence of an acidic substance 4. A .process for producing chroman compounds which comprises reacting a gamma-gamma dialkyl-substituted allylic alcohol having a double bond in the beta-gamma position to the hydroxyl group and a mono ester 01' an alkyl substituted para-di-hydroxy benzene having one position vacant ortho to the free hydroxyl group, in the presence of an acidic substance, and then cleaving the ester group from the reaction productto reintroduce the hydroxyl group.

5. A process for. producing chroman compounds which comprises-reacting a gamma-gamma dialkyl-substituted allylic alcohol having a double bond in the beta-gamma position to the hydroxyl group and a mono ether of, an alkyl substituted para-.di-hydroxy benzene having one position vacant ortho to the free hydroxyl group, in the presence of an acidic substance.

6. A process for producing chroman compounds which comprises reacting a gamma-gamma dialkyl-substituted allylic alcohol having a double bond in the. beta-gamma position to the hydroxyl or an alkyl substituted group and a mono ether and an unsubstituted positicn ortho .to said hydroxyl and selected from the pages 157-65.

esters, in the presence of zinc chloride.

para-di-hydroxy benzene having one position vacant of an acidic substance, and then cleaving the ether group from the reaction product to .reintroducethe hydroxyl group. 1

7. A process for producing chroman compounds comprising reacting a gamma-gamma-di-alkyl substituted allylic alcohol having a double bond in the beta-gamma position to the hydroxyl group, with an aromatic compound containing a free hydroxyl group and an unsubstituted position ortho to said hydroxyl and selected from the group consisting of alkyl-substituted-para-di-hydroxy-benzenes and their mono others and mono 8. A process for producing a ch'romane in which a gamma-gamma dialkyi-substituted allylio a1- cohol having a double bond in the beta-gamma position to the hydroxyl group is reacted with an aromatic compound containing a free hydroxyl group and an unsubstituted position ortho to said hydroxyl and selected from the group consisting of alkyl-substituted para-dihydroxy-benzenes,

under acidic conditions. i

LEE IRVIN SMITH. HERBERT E. UNGNADE.

REFERENCES CITED The following references are of record in the file of this patent:

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Karrer, Helvetica Chemica Acta, vol. 21 (1938) ortho to the free hydroxyl group, in the 1 presence Abstracts, 23, pages 7 

